Search Results (305)

Background/Objectives: Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder caused by recurrent upper-airway collapse during sleep, leading to intermittent hypoxia, sleep fragmentation, and excessive daytime sleepiness. Although continuous positive airway pressure (CPAP) remains the first-line therapy, long-term adherence is often suboptimal, underscoring the need for more tolerable and flexible treatment options. This review aims to summarize the pathophysiological rationale for pharmacotherapy in OSA and to discuss recent developments in drug-based interventions. Methods: We conducted a narrative review of the literature on pharmacological interventions for OSA, with a systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov up to 4 August 2026. We included randomised controlled trials, observational studies, meta-analyses, and mechanistic human or animal studies that reported relevant sleep and respiratory outcomes, and graded evidence according to the principles of GRADE framework. Results: Several drug classes have shown promise: agents that increase upper-airway dilator muscle activity, respiratory stabilizers that reduce loop gain, medications that raise the arousal threshold, topical anti-inflammatory drugs for mucosal edema, and systemic metabolic modulators such as glucagon-like peptide-1 receptor agonists and dual incretin receptor agonists. Emerging strategies, including gene therapy directed at the hypoglossal motor system, are also under investigation at the preclinical stage. Moreover, combining pharmacotherapy with CPAP or other devices can produce synergistic benefits, enabling lower device pressures and enhanced patient comfort. Conclusions: Pharmacotherapy for OSA is progressively moving from exploratory research towards targeted, phenotype-driven personalized treatment. Future studies should focus on robust patient phenotyping, multi-mechanistic combination regimens, and long-term clinical outcome evaluations to facilitate the integration of drug-based therapies into routine OSA management, particularly in specific subgroups such as those with COMISA. Full article

Background/Objectives: Systemic mastocytosis (SM) is a rare clonal mast cell disorder associated with mediator-related symptoms and a broad range of neurocognitive and sleep-related complaints. Fatigue, insomnia, and brain fog are frequently reported in clinical practice, but objective polysomnographic data in this patient population remain limited. As overweight and obesity are established contributors to sleep-disordered breathing, polysomnography (PSG) findings in patients with SM should be interpreted with caution when a control group is not available. This study aimed to characterize sleep architecture, sleep continuity, and sleep-disordered breathing in adult patients with SM who underwent PSG. Methods: This single-center observational study included nine adult patients diagnosed with SM from the Ege University Mastocytosis Database between January 2023 and January 2024. No control group was included. All patients underwent overnight laboratory PSG after discontinuation of antihistamine therapy for at least seven days. Demographic characteristics, SM subtype, baseline serum tryptase levels, Epworth Sleepiness Scale (ESS) scores, and brain fog-like cognitive complaints were recorded. PSG parameters included total sleep time, sleep efficiency, sleep onset latency, wake after sleep onset, rapid eye movement (REM) latency, sleep stage distribution, arousal burden, apnea–hypopnea index (AHI), oxygenation parameters, and periodic limb movements. Results: The study included four women and five men, with a median age of 50 years. Eight patients had a body mass index (BMI) ≥ 25 kg/m², indicating that the cohort was predominantly overweight or obese. The most common SM subtype was indolent SM. The median baseline serum tryptase level was 55.9 ng/mL, and the median ESS score was 9. Only two patients had excessive daytime sleepiness according to ESS > 10, whereas six patients reported brain fog-like complaints. Median sleep efficiency was 91.4%, total sleep time was 344 min, sleep onset latency was 9 min, and wake after sleep onset was 11 min. Median REM latency was 128.5 min. Sleep stage distribution showed median N1, N2, N3, and REM sleep proportions of 3%, 54%, 26%, and 16.7%, respectively. One patient had no observed REM sleep, and two patients had no measurable N3 sleep. The median number of arousals was 55. The median AHI was 8.2 events/hour. Although eight of nine patients met PSG criteria for obstructive sleep apnea (OSA), including five with mild and three with severe disease, this finding should be interpreted in the context of the high prevalence of overweight/obesity in the cohort. All patients with BMI ≥ 25 kg/m² had OSA, whereas the only normal-weight patient did not. Conclusions: In this single- center observational study, PSG demonstrated frequent sleep-disordered breathing, REM-related changes, and variable arousal burden in patients with SM; however, these findings cannot be separated from the predominance of overweight/obesity and the absence of a control group. Brain fog-like complaints were common, although excessive daytime sleepiness was present in only a minority of patients. Because most patients were overweight or obese and no control group was included, these findings cannot be attributed directly to SM. However, the results suggest that objective sleep assessment may be useful in selected patients with SM, particularly when fatigue, non-restorative sleep, or cognitive complaints are present. Larger controlled studies with BMI-matched groups are needed to clarify the relationship between SM, mast cell mediator activity, and sleep abnormalities. Full article

Electrodermal activity (EDA) has emerged as a promising physiological measure for objectively assessing neurodevelopmental disorders (NDDs) and related disorders, yet its effectiveness across conditions remains unclear. Following PRISMA guidelines, this review analyzed 23 studies (ASD: 11 studies, 410 participants; ADHD: 7 studies, 900 participants; OCD: 5 studies, 154 participants) published between 2010 and 2024 with a focus on methodology, including measurement protocols, signal processing, and analytical approaches. EDA demonstrated utility for diagnostic differentiation, predictive modeling, and physiological evaluation across conditions, with consistent patterns of heightened social arousal in ASD, medication-responsive sympathetic differences in ADHD, and impaired fear extinction in OCD. Machine learning approaches improved performance when combining EDA with multimodal physiological measures. However, substantial methodological heterogeneity existed across devices, recording sites, sampling frequencies, and signal processing, with 11 studies lacking signal processing details and 10 omitting sampling frequencies. The absence of standardized cross-disorder comparisons limited identification of disorder-specific versus shared autonomic signatures. While wearable technologies can enable continuous real-world monitoring, motion artifacts and signal quality remain challenges. Overall, standardized protocols and larger multimodal longitudinal studies are needed to establish EDA as a clinically useful biomarker for disorder assessment and personalized interventions. Full article

This article proposes a general integrative model focusing on psychological control and psychological reserve. The former refers to internal psychological control and external psychological control. Internal psychological control refers to the management of physiological processes associated with arousal and panics. Here, the concept of internal psychological control is differentiated into two components: cognitive control/executive function and self-control/emotional regulation. External psychological control refers to the sense the person has of being able to manage, have agency in, and otherwise not be overwhelmed by the external context in which one is adapting functionally. Here, the concept of external psychological control is differentiated into two major sub-components: managing reactivity to external events, such as to daily stressors or extreme events, e.g., natural disasters, and proactively taking steps to have agency in and using predictive processing to adjust to context by mitigating the probability of experiencing overwhelming events. Psychological reserve refers to the fluid state reservoir of mental, cognitive, emotional, motivational, and stress management/coping space that is available for use in confronting ongoing and new stressors, challenges, or difficulties. Here, this article differentiates psychological reserve into phases of depletion and recovery. This article examines prior work on psychological control and reserve, demonstrating how they can be understood or modified based on the present sub-component differentiation of the concepts involved. The revised model is applied to understanding psychotherapeutic change mechanisms, a biopsychosocial model of the mechanisms, an integrated functional adaptational model, posttraumatic stress disorder, a unified model for psychotherapy and psychology generally, and clinical recommendations. Full article

Background/Objectives: Obsessive–compulsive disorder (OCD) is associated not only with obsessions and compulsions, but also with cognitive dysfunction involving inhibitory control, cognitive flexibility, working memory, attention, decision-making, feedback learning, and performance monitoring. Electroencephalography (EEG), event-related potentials (ERPs), quantitative EEG, and time–frequency analyses provide temporally precise methods for examining how these cognitive abnormalities unfold during information processing. This review aimed to synthesise electrophysiological evidence on the neural correlates of cognitive dysfunction in OCD. Methods: A systematic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science Core Collection, Embase, PsycINFO, and Google Scholar from database inception to 30 May 2026. Eligible studies included patients with OCD and used EEG, qEEG, spectral EEG, EEG connectivity, or ERP methods in relation to cognitive performance, cognitive task demands, or cognitive dysfunction. Studies were grouped according to electrophysiological modality and ERP component. Because of methodological heterogeneity, findings were synthesised narratively and mechanistically rather than by meta-analysis. Methodological quality was assessed using ROBINS-I. Results: The search identified 1321 records, of which 42 studies met the inclusion criteria. Most studies used task-based ERP paradigms, while fewer examined resting-state EEG, qEEG, or oscillatory activity. The most consistent findings concerned altered performance monitoring and cognitive control, especially ERN, N2/N200, Pe, Pc, and P3/P300 abnormalities. ERN findings suggested excessive early error monitoring, whereas N2/N200 and P3/P300 findings indicated task-dependent abnormalities in inhibition, conflict processing, attentional allocation, stimulus evaluation, and context updating. Earlier components, including P50, N1/N100, P2/P200, and N450, suggested abnormalities in sensory gating, early attentional selection, stimulus evaluation, and interference control, particularly under emotionally salient or OCD-relevant conditions. FRN findings indicated altered feedback processing and reinforcement learning, while limited P600 evidence suggested inefficient working-memory preparation. Plain EEG and time–frequency studies further implicated abnormal theta, alpha, beta, and delta activity in monitoring, inhibition, arousal, and network efficiency. Conclusions: EEG-based evidence suggests that cognitive dysfunction in OCD reflects a dysregulated control system rather than a general reduction in cognitive ability. The disorder appears to involve excessive performance monitoring, abnormal sensory and attentional gating, inefficient inhibition, altered feedback evaluation, and reduced cognitive flexibility. However, the current evidence is limited by heterogeneity in samples, paradigms, EEG methodology, medication status, and statistical approaches. Future studies should use larger, well-characterised samples, standardised EEG/ERP paradigms, direct brain–behaviour analyses, and longitudinal designs to clarify whether electrophysiological abnormalities represent trait markers, state-dependent effects, compensatory mechanisms, or clinically useful predictors of cognitive dysfunction in OCD. Full article

Introduction: Children with Down syndrome (DS) are at increased risk of sleep-disordered breathing (SDB), but clinical correlates of polysomnography-derived severity remain incompletely defined. Objectives: This retrospective clinical–polysomnographic cohort study examined associations between selected demographic, anthropometric, cardiac, and otolaryngological variables and SDB severity metrics in children and adolescents with DS. Materials and Methods: Forty-eight participants aged ≤ 18 years underwent overnight polysomnography for suspected SDB. Respiratory events were scored according to paediatric AASM criteria; hypopnoeas required a ≥30% airflow reduction associated with ≥3% oxygen desaturation and/or arousal, and ODI was calculated using ≥3% desaturation events per hour of total sleep time. Outcomes included Apnoea–Hypopnoea Index (AHI), ODI, minimum SpO₂, and time with SpO₂ < 90%. Results: OSA was highly prevalent: AHI ≥ 1 event/h was observed in 93.8% of participants, AHI ≥ 5 events/h in 58.3%, and AHI ≥ 10 events/h in 35.4%. Mean AHI was 10.51 ± 11.82 events/h, and mean ODI was 7.07 ± 9.31 events/h. Age at PSG was not significantly associated with AHI. AHI correlated with ODI, and clinically documented adenoidal hypertrophy correlated with both AHI and ODI. Males showed significantly higher ODI values than females, whereas sex differences in AHI, minimum SpO₂, and time with SpO₂ < 90% were not significant. In exploratory multivariable models, adenoidal hypertrophy was associated with higher ODI, while adenotonsillectomy was associated with lower minimum SpO₂. Conclusions: The association between atrioventricular canal defect and hypoxaemic burden was not robust in bootstrap analyses. These exploratory findings do not warrant changes to current screening management strategies, but support further prospective studies incorporating standardised ENT and cardiac characterisation. Full article

Background: A systematic review and meta-analysis of polysomnographic sleep parameters in bipolar disorder was conducted using articles identified through searches of major databases from inception to 5 May 2026. Methods: One hundred and seven studies were identified in the systematic review. Forty-three case-control studies with 670 bipolar patients, 520 healthy controls and 280 patients with unipolar depression were eligible for the meta-analyses. Total sleep time, sleep onset latency, sleep efficiency, wake after sleep onset, REM time and percentage, REM latency, REM density, stage 1, 2, time and percentage, slow wave sleep (DELTA) time and percentage of drug-free patients with bipolar disorder were compared with case-control data of healthy controls and drug-free patients with unipolar depression. The primary outcome was the standard mean difference. Data were fitted with a random effects model. Publication bias assessment was checked by Egger’s regression and funnel plot asymmetry Results: Total sleep time and sleep efficiency were reduced in both manic and depressive drug-free bipolar patients compared with healthy controls. Delta sleep time and percentage were reduced only in the depressive patients, whereas the manic patients showed decreased stage 2 sleep time, reduced REM sleep time, shortened REM latency and increased REM density. Drug-free patients with unipolar depression showed reduced total sleep time and increased REM density compared with drug-free patients with bipolar depression. Drug-treated bipolar patients showed no differences compared with healthy controls, except for reduced % REM, increased REM latency and increased REM density. Conclusions: The results confirm the presence of sleep alterations in bipolar disorder. Although sleep duration is reduced in both manic and depressive patients, reduced delta sleep in depressive patients and increased activity/pressure of REM in manic patients appear to characterize the two phases of the illness. Altered monoaminergic activity during the depressive phase and increased cholinergic activity during the manic phase might possibly be linked to the sleep alterations also contributing to the mood changes and switch mechanisms. Full article

The assessment of consciousness has been shaped largely by research on acquired disorders of consciousness after acute or chronic brain injury, but similar problems of unreliable behavioral expression increasingly arise in neurodegenerative disease. This translational overlap is especially relevant when preserved cognition, awareness, or intentionality cannot be reliably expressed because of severe motor impairment, fluctuating arousal, cognitive decline, aphasia, apraxia, or impaired cooperation. In neurodegenerative disease, degeneration of arousal systems, large-scale brain networks, cognition, and motor pathways may similarly make observable behavior an unreliable measure of awareness. The challenge is not only to determine if a patient responds, but also to ask if residual awareness, intentionality, or covert cognition can still be detected through physiological signals. This review discusses how contemporary modalities reshape this assessment. Electroencephalography has moved from a descriptive measure of background activity to a bedside tool capable of probing event-related responses, network organization, and cortical complexity. Magnetic resonance methods reveal altered connectivity within thalamocortical and default mode network systems, while functional near-infrared spectroscopy adds a portable hemodynamic approach that may be repeated at the bedside and integrated with active paradigms. Brain–computer interfaces provide a translational step by converting neural responses into evidence of command following or, in selected patients, into communication, and artificial intelligence strengthens these approaches by extracting clinically meaningful patterns from complex neural and hemodynamic data. Additionally, autonomic measures, including heart rate variability and baroreflex indices, are considered as auxiliary physiological context for arousal and engagement, and not as direct markers of awareness. Because the most mature evidence for covert awareness and cognitive-motor dissociation comes from acquired disorders of consciousness, this review treats brain injury literature as a methodological foundation instead of as directly interchangeable evidence for neurodegenerative disease. It then examines how these approaches may be adapted to neurodegenerative contexts, especially ALS, severe dementia, Lewy body disease with fluctuating cognition, and conditions in which communication or motor output becomes unreliable. Full article

Anxiety disorders pose an increasing challenge to the mental health of individuals, particularly in regions with limited healthcare access. This study investigated the potential of integrating a brain–computer interface for processing electroencephalography (EEG) data with deep learning models to accurately classify anxious and non-anxious states. In the first phase, a convolutional neural network (CNN) was developed and validated on the public GAMEEMO dataset, achieving a classification accuracy of 95.72%. In the second phase, we conducted a separate experimental validation with seven participants (aged 18–60 years) using a within-subjects design. The protocol comprised a custom Stroop test to elicit acute cognitive stress and anxiety-related arousal, followed by a guided 4–7–8 breathing exercise to induce relaxation. EEG data from this experiment were used to classify anxious versus non-anxious states with the same CNN architecture after domain adaptation. On this self-collected dataset, the CNN achieved an accuracy of 86.58%. These results demonstrate proof-of-concept transferability while highlighting the performance gap between controlled benchmark data and real-world, small-sample recordings. The deep learning model can subsequently be coupled with neurofeedback techniques to manage anxiety levels. Overall, the findings support the potential of the developed automated system for detecting stress-induced anxious states, with possible future integration into neurofeedback-based management systems. Full article

The comorbidity of obesity and anxiety represents a complex condition with substantial health implications, exacerbating metabolic burden while compromising psychological well-being. Neurons in the lateral hypothalamus (LH) synthesize orexin-A and orexin-B, neuropeptides that orchestrate feeding behavior and energy expenditure, thereby directly regulating energy homeostasis and associated behaviors. Functioning as integrative modulators, orexins coordinate autonomic, neuroendocrine, arousal, reward, and stress circuits. Dysregulation of orexin signaling is strongly implicated in metabolic disorders, particularly obesity, as well as in psychiatric conditions including anxiety and depression, highlighting its central role in their comorbidity. This review provides a comprehensive overview of recent advances in understanding orexin-A neural circuits in feeding regulation, emphasizing mechanistic insights into the interplay between orexin signaling, energy balance, and anxiety–obesity comorbidity. Furthermore, it critically evaluates sources of heterogeneous therapeutic outcomes and outlines future strategies for precise modulation of the orexin system to restore metabolic and emotional homeostasis. Full article

Background: Sleep-disordered breathing (SDB) is frequently accompanied by autonomic nervous system (ANS) dysfunction, which is closely associated with an increased incidence of cardiovascular diseases and elevated mortality risk. Heart rate variability (HRV) serves as a classic metric for evaluating sympathovagal balance; however, the specific impacts of four distinct types of respiratory events—obstructive apnea (OA), central apnea (CA), mixed apnea (MA), and hypopnea (HYP)—on HRV remain underinvestigated. Utilizing ultra-short-term HRV analysis, this study aimed to evaluate the immediate effects of different respiratory events on ANS function, while further exploring the modulatory roles of arousal, Apnea–Hypopnea Index (AHI) severity and sleep stages (non-rapid eye movement [NREM] vs. rapid eye movement [REM]). Methods: A total of 108 patients with SDB undergoing overnight polysomnography (PSG) were included. A total of 19,862 respiratory events, including obstructive apnea (OA), central apnea (CA), mixed apnea (MA), and hypopnea (HYP), were analyzed using 15 s ECG segments. Linear mixed-effects models (LMMs) and estimated marginal means (EMMs) with Sidak-adjusted pairwise comparisons were constructed to evaluate differences in ECG-derived features and to analyze differences between event types. Results: Central apnea (CA) was associated with significantly reduced HRV and heart rate indices, including Standard Deviation of Successive Differences (SDSD), Root Mean Square of the Successive (RMSSD), Standard Deviation 1 (SD1), and heart rate (HR), compared with other respiratory event types (all p < 0.05). Across all event types, HRV metrics exhibited consistent dynamic changes before, during, and after respiratory events (all p < 0.001), characterized by a decrease during the event followed by post-event recovery. In the interaction effect of sleep stage, SDSD was significantly lower in CA compared with both OA (estimate = −11.67, 95% CI −18.78 to −4.59, p < 0.001) and HYP (estimate = −11.38, 95% CI −18.55 to −4.20, p < 0.001) during NREM sleep. No significant differences in HRV parameters, heart rate, or QRS duration were observed between OA and HYP (all p > 0.05). Conclusions: This study is the first to elucidate the differential impacts of four distinct types of sleep respiratory events on ultra-short-term HRV, confirming that CA events exert the most profound effects on autonomic function. These findings suggest that the proportion of CA occurrences could serve as a more precise biomarker for identifying individuals at high risk for cardiovascular diseases within the SDB population. Full article

Background/Objectives: Tourette syndrome and other chronic tic disorders are neurodevelopmental conditions characterized by intermittent motor/phonic tics and frequent behavioral comorbidity. Poor sleep quality is often reported by patients with tic disorders; however, little is known about the prevalence and clinical correlates of disruption in sleep physiology. Methods: We conducted a systematic literature review of clinical studies evaluating sleep using at least one validated sleep outcome (questionnaire, polysomnography, or coded clinical diagnosis). Results: Despite high heterogeneity in age ranges, diagnostic formulations, outcome measures, and confounder handling, converging evidence across designs indicated a significantly higher prevalence of sleep disturbance in patients with Tourette syndrome and other chronic tic disorders compared to controls. Specifically, registries showed significantly greater insomnia rates (aOR 6–7); case–control studies revealed a 9-fold increase in night-waking, bedtime resistance, parasomnias, and daytime drowsiness; polysomnography studies demonstrated sleep fragmentation, with decreased efficiency, longer latency, and more awakenings. Conclusions: Sleep disorders are relatively common in patients with Tourette syndrome and other chronic tic disorders, with clinical implications for both arousal instability and sleep initiation/maintenance issues. Further research is needed to better understand the complex interplay between altered sleep patterns and tic expression, as well as the impact of behavioral comorbidities. Our findings highlight a need for personalized treatment interventions focusing on sleep problems in the context of tic disorders. Full article

Anxiety disorders are disabling and treated with cognitive-behavioral or exposure-based psychotherapy. However, many patients remain symptomatic, fail to remit, relapse, or discontinue treatment. This narrative review examined whether psychotherapy non-response, defined here as persistent clinically significant anxiety symptoms, avoidance, or functional impairment after an apparently adequate psychotherapy trial, may reflect mismatch between therapeutic mechanisms and the dominant processes maintaining anxiety, and aimed to develop a usable taxonomy of mechanistic non-response. This structured narrative review followed SANRA principles. PubMed/MEDLINE, Scopus, PsycINFO, Web of Science, and the Cochrane Library were searched for peer-reviewed literature published from 1 January 2000 to 30 April 2026, including selected earlier landmark studies. Clinical, experimental, neurobiological, psychophysiological, process, and theoretical evidence were synthesized narratively. Psychotherapy mechanisms were organized around inhibitory learning, cognitive reappraisal, attentional modulation, emotion regulation, avoidance reversal, and interpersonal learning. Anxiety maintenance was multilevel, involving threat neurocircuitry, stress-related learning conditions, intolerance of uncertainty, attentional threat capture, safety behaviors, avoidance reinforcement, developmental adversity, and attachment insecurity. Non-response was framed as mismatch between the dominant maintaining process and the therapeutic mechanism expected to modify it. Six failure modes were identified: impaired inhibitory learning, cognitive rigidity/intolerance of uncertainty, stress-related learning impairment, attentional dysregulation, attachment-related barriers, and chronic avoidance dominance. Psychotherapy non-response in adult anxiety disorders should prompt mechanistic reformulation rather than repetition of the same intervention or labeling as treatment resistance. The taxonomy links recognizable failure signatures to mechanism-matched adaptations: redesigned exposure, uncertainty-focused work, attentional interventions, sequencing when arousal or sleep impairs learning, relational repair, and reduction in avoidance contingencies. The narrative review provides a concise clinical taxonomy and practical mechanism-matched adaptations to guide reformulation and treatment redesign after psychotherapy non-response in routine care. The taxonomy supports mechanism-matched reformulation after psychotherapy non-response and requires prospective validation. Full article

Objective: Recent research has expanded the understanding of the potential role of sympathetic nervous system activation in the implications of sleep-related movement disorders, particularly in the mechanisms of dopaminergic dysfunction and iron deficiency. This multifactorial perspective aims to provide insights into disease mechanisms and opportunities for targeted interventions that address both neurological and autonomic contributors to sleep-related movements. Methods: To synthesize the current evidence on the role of sympathetic activation in sleep-related movement disorders, we conducted a review of the literature to identify studies exploring the intersection of autonomic nervous system activity and motor phenomena during sleep. Results: Studies indicate that sympathetic activation may contribute directly to the initiation and propagation of motor events during sleep. Evidence from electrophysiological studies and heart rate variability analyses in patients with sleep-related movement disorders shows that sympathetic bursts often precede or coincide with leg movements and arousals, suggesting a causal rather than reactive role. Moreover, iron deficiency appears to exacerbate both dopaminergic and autonomic dysfunction, providing a unifying mechanism that bridges these pathways. Conclusions: These findings support a shift from viewing sympathetic activity as a secondary response to arousal to recognizing it as a possible primary trigger of sleep-related motor events. Full article

Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and difficult-to-control worry. The Contrast Avoidance Model (CAM) proposes that individuals with GAD use worry to sustain negative emotional arousal, thereby avoiding sharp negative emotional contrasts that would otherwise follow unexpected adverse events. A virtual reality (VR) protocol was developed to simulate such contrasts by alternating guided relaxation with brief anxiety-inducing scenarios (skyline plank, crowded elevator, and loose dog encounter). This study evaluated the usability and feasibility of this protocol in 20 subclinical adults aged 18–45 who met a screening threshold of GAD-7 ≥ 5, using a Meta Quest 3 headset and Polar H10 heart rate sensor. Exposure segments produced a significant decrease in RMSSD (β = −0.185, p < 0.001), consistent with reduced parasympathetic activity during exposure, whereas heart rate did not differ significantly between conditions. Subjectively, exposure increased SUDS (β = 2.23, p < 0.001) and SAM arousal (β = 1.95, p < 0.001), and decreased SAM valence (β = −2.68, p < 0.001) and dominance (β = −1.70, p = 0.005). Presence scores, cybersickness ratings, and qualitative feedback supported the usability of the protocol and identified concrete design refinements. These results support the feasibility of the protocol and provide a foundation for future controlled clinical evaluation. Full article